Project Summary Chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoking, is the third leading cause of death in the United States. Remarkably, individuals with similar smoking histories have different susceptibility to develop the disease, and patients display a variable degree of clinical manifestations. Genetic factors may account for these differences, but the functional, cellular and molecular basis of the variation remains to be explored. This project aims to bridge knowledge from the genome-wide association studies (GWAS) of COPD to the pathophysiological mechanisms of the disease by utilizing the observations that (1) inflammatory response is one of the most prominent differences upon cigarette smoke exposure and (2) a genetic animal model based on GWAS recapitulates the prominent features of a severe inflammatory response in COPD. Specifically, we found that genetic mouse models deficient of Hedgehog interacting protein (HHIP), a gene consistently associated with COPD in GWAS, not only recapitulate robust emphysema susceptibility, but display a strong inflammatory phenotype similar to human COPD. In particular, an increase in activated CD8+T cells is observed along the course of emphysema development. Preliminary studies using single cell RNA sequencing showed that Hhip expression is restricted to lung fibroblasts and absent from immune cells including the lymphocytes. Moreover, Hhip deficient lung fibroblasts have increased expression of cytokines known to activate CD8+T cells. These findings led us to hypothesize that reduced HHIP expression in lung fibroblasts leads to an increase in cytokines and activation of CD8+T cells, and these activated CD8+T cells play a major role in parenchymal destruction (emphysema). We propose to investigate this hypothesis by the following specific aims: 1. Determine whether CD8+T cell activation depends on Hhip in lung fibroblasts, 2. Determine the functional importance of lymphocytic activation induced by Hhip-deficiency in smoke-induced lung inflammation and 3. Determine the relationships between HHIP risk locus and pulmonary lymphocytic inflammation in human subjects. Dr. Yun will perform this work under the mentorship of Dr. Hersh, an expert in the field of COPD genomics, Dr. Zhou, an expert in the field of functional genomics, and Dr. Silverman, an expert in COPD genetic epidemiology. With the guidance of her mentors and scientific advisory committee composed of distinguished scientists with expertise related to key areas of this proposal including lung immunology, functional validation and biostatistics, Dr. Yun has developed a comprehensive five-year training program. This K08 award will support Dr. Yun to develop the skills needed to become an independent physician-scientist with the long-term goal of understanding how genetic variation modifies COPD by bridging human ?omics data and functional validation of candidate genes.